Oncogenic activation of RAS, AKT and other growth signaling pathways induces reactive oxygen species (ROS) and DNA replication stress, both of which cause DNA damage and senescence at early stages of cancer. In cultured human cells, high concentrations of glucose that mimic the effects of hyperglycemia also activate AKT signaling and induce ROS, DNA damage and senescence. Chronic hyperglycemia associated with diabetes and high carbohydrate diets is a risk factor for cancer and likely contributes to aging in humans.

My laboratory is investigating how DNA damage and cellular senescence arise downstream of the sustained activation of growth signaling by glucose and whether DNA damage induced by high glucose contributes to cancer. DNA damage and senescence that depends on AKT signaling are also induced by glucose in the model organism S. cerevisiae (budding yeast) in parallel with a shorter chronological lifespan. We recently reported that in addition to inducing elevated ROS, activation of RAS and AKT pathways by glucose in S. cerevisiae triggers replication stress and DNA damage in cells in stationary phase1-3. Both replication stress and oxidative stress induced by glucose may contribute to the chronological age-dependent activation of retrotransposons in S. cerevisiae recently discovered by others in collaboration with our laboratory4. Our laboratory and collaborators in Portugal have also determined that caloric restriction imposed by reducing the concentration of glucose extends the chronological lifespan of S. cerevisiae by reducing intracellular levels of one form of ROS – superoxide anions – via a hormesis-like mechanism that triggers elevated levels of a different form of ROS (hydrogen peroxide), which activates superoxide dismutases5. We are investigating potential connections between these findings and the first NADPH oxidase discovered recently in S. cerevisiae in a collaboration between our laboratory and several laboratories in Europe6. We also recently established that caloric restriction attenuates replication stress, in addition to attenuating oxidative stress, and that replication stress induces oxidative stress in the form of superoxide anions3. Superoxide anions also inhibit exit from S phase in stationary phase, thus inducing replication stress2,6. The complex interplay between oxidative stress and replication stress revealed by these studies points to the existence of regulatory loops triggered by glucose signaling or oncogene activation that amplify both oxidative and replication stress (Fig. 1).

In addition to an elevated risk of developing cancer, patients with diabetes also exhibit elevated sister chromatid exchanges, which are initiated at damaged replication forks. Current efforts in our laboratory are focused on determining whether chronic hyperglycemia induces replication stress and DNA damage in specific regions of human chromosomes that are frequently mutated in tumors. Glucose-induced replication stress and DNA damage could represent a previously unknown link between cancer and aging and high carbohydrate western diets.

Maxwell PH, Burhans W, Curcio MJ. Retrotransposition is associated with genome instability during chronological aging.Proceedings of the National Academy of Sciences of the United States of America 2011; 108(51): 20376-20381.